: Adenosine administered as an aerosol to asthmatics causes bronchoconstriction, while in non-asthmatics adenosine causes bronchodilation. This occurs because the activation of A2B adenosine receptors on sensitized mast cells triggers degranulation, releasing histamine, leukotrienes, and other allergic mediators. A2B adenosine receptors are blocked by theophylline, a xanthine that is effective in treating asthma. However, theophylline is a non-selective antagonist of all four adenosine receptor subtypes and produces side effects due primarily to A1 receptor blockade, including insomnia and diuresis. The incidence of asthma is increasing and current treatment options are limited. New drugs that are potent and selective antagonists of A2B adenosine receptors have great potential for the treatment of asthma and other allergic diseases. Adenosine Therapeutics, LLC owns the first potent and selective A2B antagonists. The purpose of this phase I proposal is to attempt to identify related structures that have improved aqueous solubility. A candidate compound will be evaluated in pharmacokinetic studies in dogs. Adenosine Therapeutics will also prepare mast cells from canine and human lung and determine if candidate compounds can prevent their degranulation. These studies are preliminary to a phase II SBIR study in which candidate compounds will be evaluated in dog models of asthma. PROPOSED COMMERCIAL APPLICATION: Potent and selective antagoists of A2B adenosine receptors have great commercial potential for the treatment of asthma and other allergic or autoimmune diseases.